Clinical Engineering

Solubility and uptake of agents.

The blood solubility of an agent is related to its blood-gas partition coefficient. The partition coefficient is a simple ratio of amounts: eg. The blood/gas coefficient is the ratio of the amount dissolved in blood to the amount in the same volume of gas in contact with that blood.

The more blood-soluble the agent (high blood-gas partition coefficient), the slower the onset of effect and the slower the patient goes to sleep. Thus a very soluble agent eg. 'Ether' will dissolve in large quantities in blood before the brain levels can rise sufficiently to produce anaesthesia. To understand this concept, think of the circulating blood volume as a large pool, soaking up agent and not allowing the brain to have any.

Sevoflurane

Sevoflurane is the inhalational anaesthetic agent most recently approved by the Food and Drug ministration (FDA). It has a low blood/gas partition coefficient that results in rapid induction and recovery from anaesthesia and precise control of the depth of anaesthesia.

These qualities make it a good choice of agent for anaesthesia in the ambulatory setting. Its lack of pungency allows for smooth induction that makes it an ideal choice for mask induction in paediatric patients.

Adverse events are similar to those seen with the other volatile agents. Sevoflurane does not sensitise the myocardium (heart muscle) to catecholamines, possibly the second neurotransmitter to be discovered, (Initially called 'sympathetic' because it was produced by stimulation of the sympathetic nerves).

There has been concern over the potential toxicity from its degradation in soda lime which yields the by-product Compound A, a potentially nephrotoxic substance. (nephrotoxic - the quality of being toxic or destructive to kidney cells). An additional concern about the potential for nephrotoxicity is due to the production of inorganic fluoride as a result of the oxidative metabolism (molecular breakdown) of sevoflurane.

Desflurane

Desflurane has a blood/gas coefficient lower than that of sevoflurane and as a result, desflurane allows for a more rapid induction and emergence than sevoflurane. Due to the high incidence of laryngospasm and coughing however, desflurane is not recommended for use for induction in paediatric patients that limits its usefulness. (Laryngospasm may be defined as a protective reflex that prevents foreign matter from getting into the larynx, trachea and lungs).

Sevoflurane has been studied in paediatric patients, and has proven to be a safe and effective agent in this population.

Enflurane

Enflurane has the lowest usage of all the agents and does not offer any advantages for its use. Therefore, it is rarely used in comparison with more modern agents.

Halothane

Halothane has historically been the agent of choice for paediatric patients and it is the least expensive agent in the class. For those reasons, it should continue to be generally used.

Isoflurane

Isoflurane use is normally limited to inpatient procedures.

Definition of anaesthetic potency [Mac]

Anaesthetic Potency = MAC: Minimal Alveolar Concentration at which 50% of the recipients move, in response to incision, slightly less (10-20%) than the concentrations required for clinical use.

Equipotency (physiochemical properties of agents relating to their potency, speed of onset and duration) in halogenated gas :1 MAC for Halothane = 0.75%Isoflurane = 1.15%Enflurane = 1.68%In practice, the actual concentration of halogenated agents that must be delivered may vary considerably by factors that alter MAC (e.g., no neuromuscular blockers, low arterial pressure, morphine). Recovery from halothane may be delayed by the production of bromide from its metabolism. Recovery from isoflurane and enflurane is equally rapid .

Respiratory mechanics

Enflurane depresses ventilation more than isoflurane, which in turn is slightly more depressant than halothane. Isoflurane does not alter airway resistance or dynamic resistance (resistance in peripheral airways). The three agents do not differ in their ability to decrease bronchospasm (restriction caused by muscular contraction in airways).

Myocardial performance and haemodynamic effects

At equipotent concentration (1-1.8 MAC), halothane and enflurane produce a dose-related myocardial depression (depresses the response of the heart muscle) but isoflurane does not. The lesser myocardial depression produced by isoflurane implies a greater margin of safety.

Isoflurane increases the heart rate slightly, particularly in young patients, resulting in tachycardia (This arrhythmia is seen on an ECG as periods of fast heart rates) in some. All halogenated agents decrease systemic arterial pressure. With halothane and enflurane, the decrease in arterial pressure is a consequence of the decrease in cardiac output, with isoflurane it is a consequence of decreased peripheral resistance.

Bronchospasm

Inhaled anaesthetic agents are known to relieve bronchospasm; diethylether and cyclopropane were used before the introduction of modern halogenated agents like halothane, isoflurane or enflurane. Today, halogenated gases are more commonly used in refractory status asthmaticus in mechanically ventilated patients.

Effects of halogenated agents in asthma are attributed to sustained bronchodilation, possibly by airway reflex blockade and a direct effect on smooth muscle. Knowledge of the properties, advantages and disadvantages of each gas is required for use in a PICU where anaesthetists are not necessarily always present.

Effect on the liver

Hepatotoxicity has not been recognised for isoflurane (Bierman 1986, Eger 1981, Johnston 1990). Halothane and enflurane are not directly toxic, but their metabolites appear to be responsible for a rare form of hepatic necrosis (Johnston 1976).

PROPOFOL Intravenous Anaesthetic

Propofol (Diprivan®) is a popular intravenous sedative-hypnotic anaesthetic widely used because of its rapid onset of action and recovery. It is structurally unrelated to other hypnotic agents, but has additive or synergistic effects with many of these compounds. The initial development of propofol began in the 1970's, and it was introduced into clinical practice in 1989 with its approval by the Food and Drug Administration. DIPRIVAN (Propofol) was introduced in the United States in 1989 by Zeneca Pharmaceuticals. It was the first of a new class of intravenous anaesthetic agents - the alkylphenols. Since then, it has become the anaesthetic of choice in many cases. Because of its rapid induction and recovery from anaesthesia, propofol has created a niche for itself in the ambulatory anaesthesia field. Similarly, propofol has become a popular neuro-anaesthesia agent because of the early ability to assess post-operative neurological outcome. Propofol has also been used for cardiac anaesthesia, sedation in the intensive care unit, and it has been used selectively in the emergency department for procedures requiring sedation. Propofol has also been used for sedation for endoscopy, ocular surgery, and dental procedures, with expanding new uses being proposed regularly.

CLINICAL PHARMACOLOGY

Propofol (2,6-diisopropylphenol) is an alkylphenol that is an oil at room temperature. It is essentially insoluble in water and is supplied as a one percent emulsion, containing 10 mg/ml of propofol. The emulsion also contains soybean oil 100 mg/ml, glycerol 22.5 mg/ml, egg lecithin 12 mg/ml, and disodium edetate 0.005%. Disodium edetate was added to retard the growth of micro-organisms, which may readily propagate in the formulation. The formulation also contains sodium hydroxide to adjust the pH to 7 to 8.5. Propofol may be stored at room temperature.

Propofol pharmacokinetics is characterized by a three compartment linear model, with fast distribution into the tissues, rapid metabolic clearance, and a slow return to the peripheral compartment. Following the initial bolus dose, propofol equilibrates between the plasma and the brain. Plasma levels, however, decline quickly as a result of high metabolic clearance and prompt distribution to the tissues. These properties account for propofol's rapid onset and short duration of action. Distribution time decreases as tissues equilibrate with plasma and become saturated. Elimination is triphasic, with the distribution half-life being 2-10 minutes; the second phase half-life being 21-56 minutes; and the terminal elimination half-life 1.5 to almost 30 hours. The last phase is not thought to be clinically significant. Mean induction time is 30 to 40 seconds after a 2.0 to 2.5 mg/kg bolus. Clinically, maintenance of adequate sedation requires a constant infusion of propofol. Discontinuation of propofol anesthesia usually results in a rapid decrease in plasma concentrations and prompt awakening. Longer anaesthesia cases or sedation in the intensive care unit may produce higher plasma concentrations and thus prolong awakening time.

Propofol is metabolised via hepatic conjugation to inactive metabolites that are excreted in the renal system. Some authorities believe that propofol may be metabolised in extrahepatic sites as well. Propofol has a clearance rate of 23-50 ml/kg/minute. The presence of hepatic cirrhosis or renal insufficiency does not appear to significantly alter its pharmacokinetics.

DIPRIVAN (Propofol) is indicated for:

Induction of general anaesthesia in adult patients and paediatric patients > 3 years of age.

Maintenance of general anaesthesia in adult patients and paediatric patients >2 months of age.

DIPRIVAN (Propofol) is approved for the induction and maintenance of anaesthesia in more than 50 countries. Safety, effectiveness and dosing guidelines have not been established for MAC Sedation or light general anaesthesia in the paediatric population. It is not indicated for use in Paediatric ICU Sedation since the safety of this regimen has not been established.

Pharmacodynamics

Pharmacodynamic properties of propofol are dependent upon the therapeutic blood propofol concentrations. Steady state propofol blood concentrations are generally proportional to infusion rates, especially within an individual patient. Undesirable side effects such as cardio-respiratory depression are likely to occur at higher blood concentrations that result from bolus dosing or rapid increase in infusion rate. An adequate interval (3 to 5 minutes) must be allowed between clinical dosage adjustments in order to assess drug effects.

The haemodynamic effects of Propofol injectable emulsion during induction of anesthesia vary. If spontaneous ventilation is maintained, the major cardiovascular effects are arterial hypotension (sometimes greater than a 30% decrease) with little or no change in heart rate and no appreciable decrease in cardiac output. If ventilation is assisted or controlled (positive pressure ventilation), the degree and incidence of decrease in cardiac output are accentuated. Addition of a potent opioid (eg, fentanyl) when used as a premedicant further decreases cardiac output and respiratory drive.

If anaesthesia is continued by infusion of Propofol injectable mulsion, the stimulation of endotracheal intubation and surgery may return arterial pressure towards normal. However, cardiac output may remain depressed. Comparative clinical studies have shown that the hemodynamic effects of Propofol injectable Emulsion during induction of anesthesia are generally more pronounced than with other IV induction agents traditionally used for this purpose.

During maintenance, propofol injectable emulsion causes a decrease in ventilation usually associated with an increase in carbon dioxide tension that may be marked depending upon the rate of administration and other concurrent medications (eg, opioids, sedatives, etc.).

During monitored anaesthesia care sedation, attention must be given to the cardio-respiratory effects of propofol Injectable Emulsion. Hypotension, oxyhemoglobin desaturation, apnea, airway obstruction, and/or oxygen desaturation can occur, especially following a rapid bolus of propofol Injectable Emulsion. During initiation of MAC sedation, slow infusion or slow injection techniques are preferable over rapid bolus administration, and during maintenance of MAC sedation, a variable rate infusion is preferable over intermittent bolus administration in order to minimize undesirable cardio-respiratory effects. In the elderly, debilitated, or ASA III/IV patients, rapid (single or repeated) bolus dose administration should not be used for MAC sedation.

Preliminary findings in patients with normal intraocular pressure indicate that Propofol injectable emulsion anaesthesia produces a decrease in intraocular pressure that may be associated with a concomitant decrease in systemic vascular resistance.

Propofol blood concentrations at steady state are generally proportional to infusion rates, especially in individual patients. Undesirable effects such as cardio-respiratory depression are likely to occur at higher blood concentrations which result from bolus dosing or rapid increases in the infusion rate.

Infusion rates should always be titrated downward in the absence of clinical signs of light anaesthesia until a mild response to surgical stimulation is obtained in order to avoid administration of Propofol injectable emulsion at rates higher than are clinically necessary. Generally, rates of 50 to 100 µg/kg/min in adults, should be achieved during maintenance in order to optimise recovery times.

Continuous Infusion

Propofol injectable emulsion 100 to 200 µg/kg/min administered in a variable rate infusion with 60%-70% nitrous oxide and oxygen provides anaesthesia for patients undergoing general surgery. Maintenance by infusion of Propofol Injectable Emulsion should immediately follow the induction dose in order to provide satisfactory or continuous anaesthesia during the induction phase. During this initial period following the induction dose higher rates of infusion are generally required (150 to 200 µg/kg/min) for the first 10 to 15 minutes. Infusion rates should subsequently be decreased 30%-50% during the first half-hour of maintenance.

Abrupt discontinuation of Propofol Injectable Emulsion prior to weaning or for daily evaluation of sedation levels should be avoided. This may result in rapid awakening with associated anxiety, agitation, and resistance to mechanical ventilation. Infusions of Propofol Injectable Emulsion should be adjusted to maintain a light level of sedation through the weaning process or evaluation of sedation level.